1,3-dioxane ethers

ABSTRACT

the invention concerns novel 1,3-dioxane ethers of the formula I, wherein R 1  includes alkyl, cycloalkyl, pheny and phenylalkyl, R 2  R 3  include hydrogen and alkyl, n is 1 or 2, m is 2, 3 or 4, p is zero, 1 or 2, and Z is carboxy or 1(H)-tetrazol-5-yl, and pharmaceutically acceptable salts thereof, for use in conjunction with their pharmaceutical compositions in the treatment of certain pulmonary and/or vascular disorders. The invention also describes various processes and intermediates for the manufacture of the novel compounds.

This is a division of application Ser. No. 06/861,590, filed May 9,1986, now U.S. Pat. No. 4,775,684.

This invention concerns novel 1,3-dioxane ethers and, more particularly,novel (2-alkoxyalkyl- and2-aryloxyalkyl-4-phenyl-1,3-dioxan-5-yl)alkenoic acids and relatedcompounds, which antagonise one or more of the actions of thromboxane A₂(hereafter referred to as "TXA₂ ") and which are of value as therapeuticagents.

It is known that TXA₂ is a potent aggregator of blood platelets and apowerful vasconstrictor. TXA₂ is also a potent constrictor of bronchialand tracheal smooth muscle. TXA₂ may therefore be involved in a widevariety of disease conditions, for example ischaemic heart disease suchas myocardial infarction, angina, cerebrovascular disease such astransient cerebral ischaemia, migraine and stroke, peripheral vasculardisease such as atherosclerosis, microangiopathy, hypertension and bloodclotting defects due to lipid imbalance, and pulmonary disease such aspulmonary embolism, bronchial asthma, bronchitis, pneumonia, dyspnoeaand emphysema. Accordingly, compounds which antagonise the actions ofTXA₂ may be expected to have therapeutic value in the prevention ortreatment of any one or more of the above mentioned diseases or anyother disease conditions in which it is desirable to antagonise theactions of TXA₂.

It is known from European patent application, publication No. 94239 thatcertain 4-phenyl-1,3-dioxan-5-ylalkenoic acids possess TXA₂ antagonistproperties.

According to the invention there is provided a 1,3-dioxane ether of theformula I set out hereinafter wherein R¹ is (1-6C)alkyl,(3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, phenyl orphenyl-(1-4C)-alkyl, the latter two of which may optionally bear one ortwo substituents selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy,hydroxy, trifluoromethyl, nitro and cyano; R² and R³ are independentlyhydrogen or (1-4C)alkyl, or together form (3-6C)polymethylene optionallybearing one or two (1-4C)alkyl substituents; n is 1 or 2; m is 2, 3 or4; p is zero, 1 or 2; and Z is carboxy or 1(H)-tetrazol-5-yl and thegroups at positions 2, 4 and 5 of the dioxane ring have cis-relativestereochemistry or a pharmaceutically acceptable salt thereof.

In the chemical formulae shown hereinafter, although a particularrelative configuration is shown, it is to be understood that this is notnecessarily the absolute configuration.

The compounds of formula I contain at least three asymmetric carbonatoms and may exist and be isolated in racemic and optically activeforms. It is to be understood that the invention includes any racemic,or optically active form, or mixture thereof, which is capable ofantagonising one or more of the actions of TXA₂, it being well known inthe art how to prepare individual optical isomers (for example bysynthesis from optically active starting materials or resolution of aracemic form), and how to determine the TXA₂ antagonist properties usingthe standard tests described hereafter.

A preferred value for n is 1 and for m is 2 or 3.

A particular value for R¹ when it is (1-6C)alkyl is, for example,methyl, ethyl, propyl; or butyl; when it is (3-8C)cycloalkyl is, forexample, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; when it is(3-8C)cycloalkyl-(1-4C)alkyl is, for example, cyclopropylmethyl,cyclopentylmethyl or cyclohexylmethyl; and

when it is phenyl-(1-4C)alkyl is, for example, benzyl or 2-phenylethyl.

A particular value for R² or R³ when it is (1-4C)alkyl is, for example,methyl or ethyl.

In general it is preferred that when R² and R³ are both alkyl, theytotal together up to 6 carbon atoms.

A particular value for an optional (1-4C)alkyl substituent when R² andR³ form (3-6C)polymethylene (for example trimethylene or tetramethylene)is, for example, methyl.

Particular values for optional substituents which may be present as partof R¹, when it is phenyl or phenyl-(1-4C)alkyl are for example:

for halogeno: fluoro, chloro or bromo;

for (1-4C)alkyl: methyl or ethyl; and

for (1-4C)alkoxy: methoxy or ethoxy.

A preferred group of compounds of the invention which is of particularinterest comprises those [2,4,5-cis]-dioxane derivatives of formula IIwherein R⁵ is (1-4C)alkyl (such as methyl, ethyl or propyl),(3-8C)cycloalkyl (such as cyclopentyl or cyclohexyl) or phenyl, thelatter optionally a substituent selected from halogeno, (1-4C)alkyl(such as methyl), (1-4C)alkoxy (such as methoxy), nitro and cyano; q is2 or 3; R⁶ and R⁷ are independently hydrogen or methyl; and Z is carboxyor 1(H)-tetrazol-5-yl; and the pharmaceutically acceptable saltsthereof.

A preferred value for Z is, for example, carboxy.

A particularly preferred value for q is 2. Specific compounds of theinvention are described in the accompanying Examples. However, of these,two compounds of particular interest are the carboxylic acids describedin Examples 6 and 7, or a pharmaceutically acceptable salt thereof.

Particular pharmaceutically acceptable salts of compounds of formula Iare, for example, alkali metal and alkaline earth metal salts, such aslithium, sodium, potassium, magnesium and calcium salts, aluminium andammonium salts, and salts with organic amines and quaternary basesforming physiologically acceptable cations, such as salts withmethylamine, dimethylamine, trimethylamine, ethylenediamine, piperidine,morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine,N-methylglucamine, tetramethylammonium hydroxide andbenzyltrimethylammonium hydroxide.

The compounds of formula I may be manufactured by conventionalprocedures of organic chemistry well known in the art for themanufacture of structurally analogous compounds. Such procedures areprovided as a further aspect of the invention and are illustrated by thefollowing processes in which R¹, R², R³, R⁴, Z, n, m and p have any ofthe meanings herein above: (a) An aldehyde of the formula III is reactedwith a Wittig reagent of the formula IVa or IVb wherein R' is(1-6C)-alkyl or aryl (especially phenyl) and M⁺ is a cation, for examplean alkali metal cation, such as the lithium, sodium or potassium cation.

The process in general produces predominantly the required compounds offormula I in which the substituents adjacent to the double bond havecis-relative stereochemistry i.e. the "Z" isomer. Any analogouscompounds having trans-relative stereochemistry about the vinylene groupmay be removed by a conventional separation procedure, for example bychromatography or crystallisation.

The process is conveniently performed in a suitable solvent or diluent,for example an aromatic solvent such as benzene, toluene orchlorobenzene, an ether such as 1,2-dimethoxyethane, t-butyl methylether, dibutyl ether or tetrahydrofuran, in dimethyl sulphoxide ortetramethylene sulphone, or in a mixture of one or more such solvents ordiluents. The process is generally performed at a temperature in therange, for example, -80° C. to 40° C., but is conveniently performed ator near room temperature, for example in the range 0° to 35° C.

(b) For a compound of formula I wherein Z is 1(H)-tetrazol-5-yl, anitrile of the formula V is reacted with an azide.

A particularly suitable azide is, for example, an alkali metal azidesuch as sodium or potassium azide, preferably together with an ammoniumhalide, for example ammonium chloride, ammonium bromide ortriethylammonium chloride. The process is preferably carried out in asuitable polar solvent, for example N,N-dimethylformamide orN-methylpyrrolidone and, conveniently, at a temperature in the range,for example, 50° to 160° C.

(c) A phenol derivative of the formula VI, wherein R" is (1-6C)alkyl(such as methyl or ethyl), acyl (such as acetyl, benzoyl,methanesulphonyl or p-toluene-sulphonyl), allyl, tetrahydropyran-2-yl ortrimethylsilyl, is deprotected.

The precise deprotection conditions used depend on the nature of theprotecting group R". Thus, for example, when it is methyl or ethyl thedeprotection may be carried out by heating with sodium thioethoxide in asuitable solvent (such as N,N-dimethylformamide or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) at a temperature inthe range, for example, 60°-160° C. Alternatively, an ethyl or methylprotecting group may be removed by reaction with lithiumdiphenylphosphide in a suitable solvent (such as tetrahydrofuran ort-butyl methyl ether) at a temperature in the range, for example, 0°-60°C. When the protecting group is acyl it may be removed, for example, byhydrolysis in the presence of a base (such as sodium or potassiumhydroxide) in a suitable aqueous solvent [such as an aqueous(1-4C)alkanol] at a temperature in the range, for example, 0°-60° C.When the protecting group is allyl or tetrahydropyran-2-yl, it may beremoved, for example, by treatment with strong acid (such astrifluoroacetic acid), and when it is trimethylsilyl, it may be removed,for example, by reaction with aqueous tetrabutylammonium fluoride orsodium fluoride, using a conventional procedure.

(d) An erythro-diol derivative of the formula VII, wherein one of Q¹ andQ² is hydrogen and the other is hydrogen or a group of the formula-CRaRb.OH (wherein Ra and Rb are the same or different (1-4C alkyl), isreacted with an aldehyde of the formula VIII wherein R¹, R², R³ and phave the meanings defined above, or with an acetal, hemiacetal orhydrate thereof.

The aldehyde of formula VIII [or its hydrate, or its acetal orhemiacetal with a (1-4C)alkanol (such as methanol or ethanol)] isgenerally used in excess.

The reaction is generally performed in the presence of an acid catalyst,such as hydrogen chloride, hydrogen bromide, sulphuric acid, phosphoricacid, methanesulphonic acid, p-toluenesulphonic acid or an acidic resin,conveniently in the presence of a suitable solvent or diluent, such astoluene, xylene or an ether, for example tetrahydrofuran, dibutyl ether,methyl t-butyl ether or 1,2-dimethoxy-ethane, and at temperature in therange, for example 0° to 80° C.

Those starting materials of formula VII wherein Q¹ and Q² are bothhydrogen may be obtained, for example, by mild acid catalysed hydrolysisor alcoholysis of the dioxane ring of a compound of formula IX whereinRa and Rb are both alkyl, such as methyl or ethyl. The hydrolysis oralcoholysis will normally be carried out a temperature in the range 10°to 80° C. using an aqueous mineral acid such as hydrochloric acid, in analkanol (such as ethanol or 2-propanol) or an ether (such astetrahydrofuran) as solvent.

The starting materials of formula VII wherein one of Q¹ and Q² ishydrogen and the other is a group of the formula -CRaRb.OH areintermediates in the above-mentioned formation of the starting materialsof formula VII wherein Q¹ and Q² are both hydrogen. However, the saidintermediates are not normally isolated or characterised. Accordingly,the invention also provides a modification of process (d) whichcomprises reacting a compound of formula IX wherein one of Ra and Rb ishydrogen, methyl or ethyl (preferably methyl or ethyl) and the other ismethyl or ethyl with an excess of a compound of the formula VIII, or anacetal, hemiacetal or hydrate thereof, in the presence of anacid-catalyst (such as one of those given above), conveniently at atemperature in the range, for example, 10° to 80° C. and optionally inthe presence of a suitable solvent or diluent (such as one of thosegiven above).

The starting materials for use in the above processes may be made bygeneral procedures of organic chemistry, known for the preparation ofstructurally related compounds, for example as described in Europeanpatent application, publication No. 94239.

The nitriles of formula V may be obtained, for example, by substitutingthe appropriate ylid of the formula R'₃ P═CH.(CH₂)_(m).CN for the ylidof formula IV in the Wittig reaction described in process (a) above. Theprotected phenol derivatives of formula VI may be made, for example, byusing an analogous procedure to process (a) above, using an aldehydeanalogous to formula III but wherein the phenol group has been protectedwith the group R". The starting materials of formula IX may be obtainedusing analogous procedures to those described in European patentapplication, publication number 94239.

The necessary Wittig reagents of formula IVa and IVb may be obtained byconventional procedures, for example by treating the correspondingphosphonium halides with a strong base, such as sodium hydride, lithiumdiisopropylamide, potassium t-butoxide or butyllithium. They aregenerally formed in situ just prior to carrying out the condensationprocess (a) above.

It will be understood that the compounds of formula I wherein Z iscarboxy may also be obtained by other conventional procedures well knownin the art for the production of carboxylic acids, for example bybase-catalysed hydrolysis of the corresponding esters, for example, thelower alkyl esters, using, for example, lithium or sodium hydroxide asthe base. Such procedures are included within the invention.

When a salt of a compound of formula I is required, it is obtained byreaction with the appropriate base affording a physiologicallyacceptable cation, or by any other conventional procedure.

Further, when an optically active form of a compound of formula I isrequired, one of the aforesaid processes is carried out using anoptically active starting material. Alternatively, the racemic form of acompound of formula I may be reacted with an optically active form of asuitable organic base, for example ephedrine,N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide or 1-phenylethylamine,followed by conventional separation of the diastereoisomeric mixture ofsalts thus obtained, for example by fractional crystallisation from asuitable solvent, for example a (1-4C)alkanol, whereafter the opticallyactive form of said compound of formula I may be liberated by treatmentwith acid using a conventional procedure for example using an aqueousmineral acid such as dilute hydrochloric acid.

Many of the intermediates defined herein are novel and are provided asfurther separate features of the invention. Certain intermediates offormula VI, especially those wherein R" is methyl and m is 2, possessuseful TXA₂ antagonist properties and such compounds together with theirpharmaceutically acceptable salts are provided as a still furtherfeature of the invention.

As stated earlier, the compounds of formula I are antagonists of one ormore of the actions of TXA₂, for example certain of its actions on bloodplatelets, the vasculature and/or the lung. The antagonism may bedemonstrated in one or other of the following standard tests:

(a) The rabbit aortal strip model devised by Piper and Vane (Nature,1969, 223, 29-35) or the rat aortal strip model developed by Kennedy etalia (Prostaglandins, 1982, 24, 667-689), using as agonist the TXA₂mimetic agent known as U46619 (described by R. L. Jones et alia, in"Chemistry, Biochemistry and Pharmacological Activity of Prostanoids"edited by S. M. Roberts and F. Scheinmann, at page 211, Pergamon Press,1979);

(b) a blood platelet aggregation test based on that described by Born(Nature, 1962, 194, 927-929) and involving:

(i) aggregating human, citrated platelet-rich plasma by addition of theTXA₂ mimetic agent U46619 so that a dose-response curve is generated;

(ii) generating a dose-response curve for U46619 stimulated plateletaggregation in the presence of increasing amounts of test compound(generally in the range, 10⁻⁵ M to 10⁻¹⁰ M); and

(iii) calculating a K_(B) value indicating potency of TXA₂ antagonismfor the test compound, averaged over several concentrations, from thecalculated 50% response value for U46619 aggregation in the presence andabsence of test compound; and

(c) a bronchoconstriction test involving measuring the inhibition bytest compound of the broncho-constriction induced in theKonzett-Rossler, anaesthetised guinea-pig model (as modified by Collierand James, Brit. J. Pharmacol., 1967, 30, 283-307) by intravenousadministration of the TXA₂ mimetic agent, U46619 and involving:

(i) obtaining a cumulative dose-response curve to U46619 inducedbronchoconstriction by intravenous administration of constant volumes ofincreasing concentrations of U46619 (0.2-4 μg/kg) in physiologicalsaline solution and expressing broncho-constriction as the maximum ofthat theoretically obtainable with no air flow to the test animal;

(ii) generating a cumulative dose-response curve to U46619 inducedbronchoconstriction at 30 minute intervals for 3 hours after oral dosingof test compound; and

(iii) calculating a dose-ratio for the test compound (that is the ratioof concentration of U46619 required to cause 50% bronchoconstriction inthe presence and absence of test compound) indicating the potency ofTXA₂ antagonism.

(d) The antagonism of the effects of TXA₂ on the vasculature may bedemonstrated, for example in rats in the following manner:

Male rats (Alderley Park strain) are anaesthetised with sodiumpentobarbital and blood pressure is monitored at the carotid artery. TheTXA₂ mimetic agent U46619 is administered intravenously via the jugularvein at 5 μg/kg to induce a 20-30 mm Hg (2640-3970 pascal) increase insystolic blood pressure. The process is repeated twice to establishreproducibility of response.

A test compound is then administered either intravenously via thejugular vein or orally via a cannula directly into the stomach and theanimal challenged with an U46619 five minutes after dosing with testcompound and then successively every ten minutes until the hypertensiveeffect of U46619 is no longer blocked.

Further, the antagonism of the effects of TXA₂ in vivo may bedemonstrated, for example, by assessing the effects of a test compoundon the aggregation of blood platelets obtained after administration oftest compound to a test animal such as a rabbit, rat, guinea pig or dog,using standard procedures similar to that described in (a) above.However, when the aggregation of dog platelets is being studied it isnecessary to use a pre-determined, threshold concentration of theplatelet aggregrant adenosine diphosphate (about 0.4-1.2×10⁻⁶ M)together with the TXA₂ mimetic agent, U46619.

By way of illustration, the compound described in Example 6 hereafterpossesses a pA₂ of 9.71 on rat aortal strip using procedure (a) andexhibits a K_(B) of 1.75×10⁻⁸ M in procedure (b) above.

In general, compounds of formula I show significant TXA₂ antagonistproperties in one or more of the above mentioned tests i.e. test (a)pA₂ >6.0; test (b) K_(B) <5×10⁻⁶ ; test (c) dose ratio >5 200 μg/kg p.o.In addition compounds of formula I may show significant activity in therat blood pressure test and/or in one or more of the ex vivo bloodplatelet tests referred to above. No significant adverse effects havebeen observed at the active doses in vivo.

As stated previously, the compounds of formula I may be used in thetherapy or prevention of diseases or adverse conditions in warm-bloodedanimals in which it is desirable to antagonise one or more of theactions of TXA₂. In general, a compound of formula I will beadministered for this purpose by an oral, rectal, intravenous,subcutaneous, intramuscular or inhalation route, so that a dose in therange, for example 0.01-5 mg/kg body weight, will be given up to fourtimes per day, varying with the route of administration, the severity ofthe condition and the size and age of the patient under treatment.

The compounds of formula I will generally be used in the form of apharmaceutical composition comprising a compound of formula I or apharmaceutically acceptable salt thereof as defined hereinbefore,together with a pharmaceutically acceptable diluent or carrier. Such acomposition is provided as a further feature of the invention and may bein a variety of dosage forms. For example, it may be in the form oftablets, capsules, solutions or suspensions for oral administration; inthe form of a suppository for rectal administration; in the form of asterile solution or suspension for administration by intravenous orintramuscular injection; in the form of an aerosol or a nebulisersolution or suspension, for administration by inhalation; and in theform of a powder together with pharmaceutically acceptable inert soliddiluents such as lactose, for administration by insufflation.

The pharmaceutical compositions may be obtained by conventionalprocedures using pharmaceutically acceptable diluents and carriers wellknown in the art. Tablets and capsules for oral administration mayconveniently be formed with an enteric coating, for example comprisingcellulose acetate phthalate, to minimise contact of the activeingredient of formula I with stomach acids.

The pharmaceutical compositions of the invention may also contain one ormore agents already known to be of value in the diseases or conditionsintended to be treated; for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionate), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

In addition to their use in therapeutic medicine, the compounds offormula I are also useful as pharmacological tools in the developmentand standardisation of test systems for the evaluation of the effects ofTXA₂ in laboratory animals such as cats, dogs, rabbits, monkeys, ratsand mice, as part of the search for new therapeutic agents. Thecompounds of formula I may also be used because of their TXA₂ antagonistproperties in helping to maintain the viability of blood and bloodvessels in warm-blooded animals (or parts thereof) under-goingartificial extracorporeal circulation, for example during limb or organtransplant. When used for this purpose, a compound of formula I, or aphysiologically acceptable salt thereof, will generally be administeredso that a steady state concentration in the range, for example, 0.1 to10 mg per liter is achieved in the blood.

The invention will now be illustrated by the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in therange 18°-26° C.;

(iii) flash column chromatography and medium pressure liquidchromatography (MPLC) were performed on Merck Kieselgel 60 (Art, 9385),monitoring the process by UV absorption or thin layer chromatography onMerck 0.25 mm Kieselgel 60F 254 plates (Art. 5715); these materials wereobtained from E. Merck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) NMR spectra were normally determined at 200 MHz in CDCl₃ usingtetramethylsilane (TMS) as an internal standard, and expressed aschemical shifts (delta values) in parts per million relative to TMSusing the following abbreviations for designation of major peaks: s,singlet; m, multiplet; t, triplet; b, broad; d, doublet; when a singlechemical shift value is given for a multiplet (m) this corresponds tothe center point of the signals making up the multiplet; and

(vi) end-products were isolated as racemates, and characterised by NMR,microanalysis, mass spectroscopy and/or other standard procedures.

EXAMPLE 1

A solution of5(Z)-7-([2,4,5-cis]-2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)heptenoicacid (1.80 g) in dry 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone(DMPU) (4 ml) was added to a stirred solution of sodium thioethoxide(2.47 g) in dry DMPU (50 ml) at 85° C. under argon. The mixture wasstirred for 2 hours, cooled to ambient temperature and poured intoice-water (150 ml). The aqueous mixture was washed with dichloromethane(2×75 ml), acidified to pH4 with 2M hydrochloric acid and extracted withether (3×100 ml). These extracts were washed successively with water(3×50 ml) and saturated brine (50 ml), then dried (MgSO₄) andevaporated. Flash chromatography of the residue, eluting withtoluene/ethyl acetate/acetic acid (75:25:02 v/v) gave5(Z)-7-([2,4,5-cis]-4-o-hydroxyphenyl-2-methoxymethyl-1,3-dioxan-5-yl)heptenoicacid, as a pale yellow oil (1.01 g); NMR: 1.63 (3H,m), 1.87 (1H,m), 2.00(2H,q J=7 Hz), 2.28 (2H, t J=7 Hz), 2.62 (1H,m), 3.45 (3H,s), 3.60(2H,m), 3.39 (1H,dm J=12,Hz), 4.14 (1H,dd J=12, 1 Hz), 4.94 (1H,t J=5Hz), 5.25 (1H,d J=2 Hz), 5.34 (2H,m), 6.90 (3H,m), 7.17 (1H,m); m/e 350(M⁺).

The necessary starting material was obtained as follows:

(i) A solution containing5(Z)-7-(2,2-dimethyl-4-o-methoxyphenyl-1,3-dioxan-cis-5-yl)heptenoicacid (10.0 g), water (33 ml) and 2M hydrochloric acid (0.5 ml) intetrahydrofuran (THF) (267 ml) was heated with stirring at 60°-70° C.for 2 hours. The solvent was then evaporated. The residue obtained wasdiluted with ether (350 ml). The mixture was washed with water (4×75ml), then with saturated brine (2×75 ml), dried (MgSO₄) and evaporated.The oil obtained was purified by flash chromatography, eluting withtoluene/ethyl acetate/acetic acid (60:40:2 v/v), to give5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-o-methoxyphenyl-5-nonenoic acidas a colourless oil which slowly crystallised to give solid (A) (8.40g), m.p. 79°-80° C.; NMR (400 MHz): 1.66 (2H,m), 1.90 (1H,m), 2.08(3H,m), 2.32 (3H,m), 3.69 (2H,m), 3.82 (3H,s), 5.22 (1H,t J=4 Hz), 5.37(2H,m), 6.88 (1H,d J=8 Hz), 6.98 (1H,t J=7 Hz), 7.25 (1H,m), 7.43(1H,dd) J=7,2 Hz).

(ii) A solution containing A (7.70 g) and ethyl acetate (10 ml) in ether(25 ml) was treated at 4° C. with an ice-cold ethereal solution ofdiazomethane until a yellow colour persisted. The solution was thentreated with acetic acid (0.2 ml) and the solvent removed in vacuo. Theresidual oil was purified by flash chromatography, eluting with 45% v/vethyl acetate/hexane, to give methyl5(Z)-erythro-9-hydroxy-8-hydroxymethyl-9-o-methoxyphenyl-5-nonenoate asa colourless oil (B) (7.83 g); NMR (400 MHz): 1.74 (2H,m), 1.89 (1H,m),2.05 (3H,m), 2.30 (3H,m), 2.47 (1H,br s), 3.13 (1H,d J=4 Hz), 3.66(3H,s), 3.68 (2H,m), 3.84 (3H,s) 5.21 (1H,t J=4 Hz), 5.37 (2H,m), 6.88(1H,d J=7 Hz), 6.99 (1H,t J=7 Hz), 7.2 (1H,m), 7.43 (1H,dd J=7,2 Hz).

(iii) A stirred solution of C (3.0 g), p-toluenesulphonic acid (20 mg)and 1,2,2-trimethoxyethane (10 ml) was heated at 90° C. for 3 hours. Thecooled reaction mixture was diluted with ether (50 ml) and washedsuccessively with 5% w/v sodium bicarbonate solution (3×20 ml), water(10 ml) and saturated brine (10 ml), then dried (MgSO₄) and evaporated.Flash chromatography of the residue, eluting with 15% v/v ethylacetate/hexane, gave methyl5(Z)-7-([2,4,5-cis]-2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)heptenoateas a pale yellow oil (D) (2.50 g): NMR: 1.60 (3H,m), 1.83 (1H,m), 1.93(2H, q J=7 Hz), 2.22 (2H,t J=7 Hz), 2.38 (1H,m), 3.46 (3H,s), 3.58 (2H,dJ=4 Hz), 3.65 (3H,s), 3.80 (3H,s), 3.96 (1H,dm J=12 Hz), 4.09 (1H,ddJ=12, 1 Hz), 4.98 (1H,t J=4 Hz), 5.22 (1H,d J=2 Hz), 5.25 (2H,m), 6.83(1H,br d J=7 Hz), 6.96 (1H,br t J=7 Hz), 7.24 (1H,td J=7, 1.5 Hz), 7.41(1H, dd J=7,1.5 Hz).

(iv) 2M Potassium hydroxide solution (20 ml) was added to a stirredsolution of D (2.50 g) in methanol (250 ml). After 20 hours, water (400ml) was added. The mixture was washed with ether (100 ml), thenacidified to pH 4 with 2M hydrochloric acid and extracted with furtherether (3×150 ml). The extracts were washed with saturated brine (2×50ml), dried (MgSO₄) and evaporated. Flash chromatography of the residue,eluting with toluene/ethyl acetate/acetic acid (75:25:0.2 v/v), gave5(Z)-7-([2,4,5-cis]-2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)heptenoicacid, as a pale yellow oil (2.05 g); NMR: 1.60 (3H,m), 1.83 (1H,m), 1.97(2H,m), 2.26 (2H,t J=7 Hz), 2.43 (1H,m), 3.46 (3H,s), 3.60 (2H,m), 3.80(3H,s), 3.96 (1H, dm J=12 Hz), 4.09 (1H,dd J=12,1 Hz), 4.98 (1H,t J=5Hz), 5.23 (1H,d J=2 Hz), 5.27 (2H,m), 6.84 (1H,dd J=7,1 Hz), 6.97 (1H,td J=7,1 Hz), 7.23 (1H,td J=7,1.5 Hz), 7.40 (1H,dd J=7,1.5 Hz).

EXAMPLE 2

A solution of4(Z)-6-([2,4,5-cis]-2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid (740 mg) in dry DMPU (5 ml) was added to a stirred solution ofsodium thioethoxide (1.008 g) in dry DMPU (25 ml) at 85° C. under argon.After 3 hours at 85° C., the reaction mixture was cooled to ambienttemperature and poured into ice-water (150 ml). The aqueous mixture waswashed with dichloromethane (3×100 ml), acidified to pH 5 with 2Mhydrochloric acid and extracted with ether (3×40 ml). These extractswere washed successively with water (15 ml) and saturated brine (15 ml),then dried (MgSO₄) and the solvent evaporated. Flash chromatography ofthe residue, eluting with toluene/ethyl acetate/acetic acid (70:30:0.2%v/v), gave4(Z)-6-([2,4,5-cis]-4-o-hydroxyphenyl-2-methoxymethyl-1,3-dioxan-5-yl)hexenoicacid as a yellow oil (329 mg), which crystallised slowly to give a solidof m.p. 103° -104° C.; NMR: 1.72 (1H,m), 190 (1H,m), 2.33 (4H,m), 2.67(1H,m), 3.44 (3H,s), 3.59 (2H,d J=4 Hz), 3.94 (1H,dm J=12 Hz), (1H,ddJ=12,1 Hz), 4.93 (1H,t J=4 Hz), 5.26 (1H,d J=2 Hz), 5.27 (1H,m), 5.43(1H,m), 6.89 (3H,m), 7.16 (1H,m); m/e 336 (M⁺).

The necessary starting material was obtained as follows:

(i) A solution of(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)acetaldehyde (15.8g) in dry THF (75 ml) was added under argon to a stirred, ice-cooledsolution of the yield prepared from(3-carboxypropyl)triphenylphosphonium bromide (51.48 g) and potassiumt-butoxide (26.88 g) in dry THF (400 ml). The mixture was stirred for 15minutes at 4° C., then for 1.5 hours at ambient temperature and was thenpoured into ice-water (1 liter). The mixture obtained was washed with50% v/v ether/hexane (2×250 ml) to remove the bulk of neutral material.The aqueous phase was acidified to pH 5 with acetic acid and extractedwith ether (4×300 ml). These extracts were washed successively withwater (3×150 ml), and saturated brine (2×100 ml), then dried (MgSO₄) andevaporated. The residue was purified by flash chromatography, elutingwith toluene/ethyl acetate/acetic acid (80:20:2 v/v). The solid obtainedwas crystallised from 10% v/v ethyl acetate/hexane (250 ml) to give4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoic acid(A) (13.0 g), m.p. 99°-101° C.; NMR: 1.52 (3H,s), 1.54 (1H,m), 1.56(3H,s), 1.80 (1H,m), 2.28 (4H,m), 2.49 (1H,m), 3.77 (1H,dd J=11,1 Hz),3.82 (3H,s), 4.16 (1H,dm J=11 Hz), 5.28 (2H,m), 5.45 (1H,d J=2 Hz), 6.83(1H,dd J=7,1 Hz), 6.97 (1H,td J=7,1 Hz), 7.22 (1H,td J=8,1 Hz), 7.48(1H,dm J=8 Hz).

(ii) A solution of A (4.20 g) in a mixture of water (12 ml), 2Mhydrochloric acid (0.5 ml) and THF (40 ml) was heated with stirring at60°-70° C. After 2 hours the mixture was cooled to ambient temperatureand poured into water (100 ml). The aqueous mixture was extracted withether (3×50 ml). The combined extracts were washed successively withwater (2×40 ml) and saturated brine (40 ml), then dried (MgSO₄) andevaporated to give4(Z)-erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acidas a colourless oil (B) (3.80 g); NMR: 1.95 (1H,m), 2.11 (1H, m), 2.37(5H,m), 3.67 (2H,m), 3.83 (3H,s), 4.84 (3H,br), 5.22 (1H,d J=4 Hz), 5.38(2H,m), 6.88 (1H,br d J=7 Hz), 6.98 (1H,bt J=7 Hz), 7.25 (1H,td J=-7,1.5Hz), 7.42 (1H,dd J=7,1.5 Hz).

(iii) A solution of B (3.70 g) in ether (65 ml) was treated at 0°-4° C.with an ice-cold, ethereal solution of diazomethane until a yellowcolour persisted. Acetic acid (0.2 ml) was then added and the solventwas evaporated. Flash chromatography of the residue, eluting with ethylacetate/hexane (45:55 v/v), gave methyl4(Z)-erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoate, asa colourless oil (C) (3.00 g); NMR: 1.90 (1H,m), 2.10 (1H,m), 2.36(6H,m), 3.20 (1H,br), 3.66 (3H,s), 3.67 (2H,m), 3.83 (3H,s), 5.23 (1H,dJ=5 Hz), 5.35 (2H,m), 6.87 (1H,br d J=8 Hz), 6.98 (1H,br t J=7 Hz), 7.24(1H,td J=8,2 Hz), 7.45 (1H,dd J=7,2 Hz).

(iv) A stirred solution containing C (1.5 g), p-toluenesulphonic acid(10 mg) and 1,1,2-trimethoxyethane (5 ml) was heated at 90° C. for 3hours. The cooled reaction mixture was diluted with ether (50 ml) andsuccessively washed with 5% w/v sodium bicarbonate solution (3×20 ml),water (10 ml), and saturated brine (10 ml), then dried (MgSO₄) andevaporated. Flash chromatography of the residual oil, eluting with ethylacetate/hexane (15:85 v/v) gave methyl4(Z)-6-([2,4,5-cis]-2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoateas a pale yellow oil (D) (865 mg); NMR: 1.60 (1H,m), 1.87 (1H,m), 2.24(4H,m), 2.45 (1H,m), 3.44 (3H,s), 3.58 (2H,d J=4 Hz), 3.64 (3H,s), 3.80(3H,s), 3.96 (1H,dm J=12 Hz), 4.08 (1H,dd J= 12,1 Hz), 4.98 (1H,t J=4Hz), 5.23 (1H,d J=2 Hz), 5.27 (2H,m), 6.83 (1H,br d J=7 Hz), 6.96 (1H,tdJ=7,1 Hz), 7.23 (1H,td J=7, 1.5 Hz), 7.42 (1H,dd J=7,1.5 Hz).

(v) A stirred solution of D (865 mg) in methanol (70 ml) was hydrolysedat ambient temperature by reaction with 2M potassium hydroxide (7.0 ml)for 4 hours. Using a similar work-up procedure to that described in part(iv) of Example 1, there was obtained4(Z)-6-([2,4,5-cis]-2-methoxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid, as a colourless oil (740 mg); NMR: 1.60 (1H,m), 1.88 (1H,m), 2.27(4H,m), 2.48 (1H,m), 3.44 (3H,s), 3.59 (2H, d J=4 Hz), 3.80 (3H,s), 3.96(1H,dm J=12 Hz), 4.09 (1H,dd J=12,1 Hz), 4.98 (1H,t J=4 Hz), 5.23 (1H,dJ=2 Hz), 5.29 (2H,m), 6.83 (1H,br d J=7 Hz), 6.96 (1H,td J=7,1 Hz), 7.23(1H,td J=7,1.5 Hz), 7.42 (1 H,dd J=7, 1.5 Hz).

EXAMPLE 3

A stirred solution of4(Z)-6-([2,4,5-cis]-2-[2-ethoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)-hexenoicacid (A) (900 mg) in dry THF (3 ml) was treated at 4° C. under argonwith a solution of lithium diphenylphosphide [prepared fromchlorodiphenylphosphine (1.59 g) and lithium metal (202 mg) in dry THF(10 ml)]. The mixture was stirred for 5 minutes at 4° C., for 3 hours at50° C., then cooled to 10° C. and added to ice-water (50 ml). Theaqueous mixture was washed with ether (2×20 ml), acidified to pH 5 withacetic acid and extracted with ether (3×30 ml). These extracts werewashed successively with water (20 ml) and saturated brine (20 ml), thendried (MgSO₄) and evaporated. Flash chromatography of the residue,eluting with toluene/ethyl acetate/acetic acid (75:25:0.2 v/v), gave4(Z)-6-([2,4,5-cis]-2-[2-ethoxyethyl]-4-o-hydroxyphenyl-1,3-dioxan-5-yl)hexenoic acid, as apale yellow oil (426 mg); NMR: 1.21 (3H,t J=7 Hz), 1.64 (1H,m), 1.88(1H,m), 2.03 (2H,m), 2.33 (4H,m), 2.66 (1H,m), 3.51 (2H,q J=7 Hz), 3.60(2H,m), 3.90 (1H,dm J=12 Hz), 4.09 (1H,dd J=12,1.5 Hz), 4.92 (1H,t J=4.5Hz), 5.20 (1H,d J=2 Hz), 5.28 (1H,m), 5.43 (1H,m), 6.87 (3H,m), 7.17(1H,td J=7,1.5 Hz); m/e 382 (M⁺ +NH₄), 365 (M⁺ +H).

The necessary starting material (A) was obtained using an analogousprocedure to that described in Example 2, parts (iv) and (v). Thus,using the procedure of Ex. 2 (iv) starting with 1,1,3-triethoxypropaneinstead of 1,1,2-trimethoxyethane, there was obtained methyl4(Z)-6-([2,4,5-cis]-2-[2-ethoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoatein 62% yield as a pale yellow oil; NMR: 1.20 (3H,t J=7 Hz), 1.59 (1H,m),1.84 (1H,m), 2.04 (2H,m), 2.26 (4H,m), 2.43 (1H,m), 3.49 (2H,q J=7 Hz),3.61 (2H, t J=7 Hz), 3.64 (3H,s), 3.80 (3H,s), 3.92 (1H,dm J=12 Hz),4.02 (1H,dd J=12,1 Hz), 4.92 (1H,t J=5 Hz), 5.18 (1H,d J=2 Hz), 5.25(2H,m), 6.83 (1H,br d J=7 Hz), 6.97 (1H,dd J=7,1 Hz), 7.23 (1H,tdJ=7,1.5 Hz), 7.43 (1H,td J=7,1.5 Hz). This ester was then hydrolysedusing the procedure of Ex. 2 (v) to give the required acid (A) as acolourless oil in 95% yield; NMR: 1.18 (3H,t J=7 Hz), 1.57 (1H,m), 1.85(1H,m), 2.02 (2H,m), 2.27 (4H,m), 2.47 (1H,m), 3.48 (2H,q J=7 Hz), 3.61(2H,t J=7 Hz), 3.80 (3H,s), 3.91 (1H,dm J=12 Hz), 4.03 (1H,br d J=12Hz), 4.92 (1H,t J=5 Hz), 5.18 (1H,d J=2 Hz), 5.29 (2 H,m), 6.83 (1H,br dJ=7 Hz), 6.97 (1H, br t J=7 Hz), 7.23 (1H,t d J=7,1.5 Hz), 7.43 (1H,ddJ=7,1.5 Hz).

EXAMPLE 4

A stirred solution of4(Z)-6-([2,4,5-cis]-2-cyclohexyloxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid (0.50 g) in dry THF (3 ml) was treated at 4° C. under argon with asolution of lithium diphenylphosphide [prepared fromchlorophenylphosphine (0.99 g) and lithium metal (0.13 g) in dry THF (5ml)]. The mixture was stirred 5 minutes at 4° C., then for 3 hours at50° C., cooled to 10° C. and added to ice-water (50 ml). The aqueousmixture was washed with ether (3×20 ml), acidified to pH5 with aceticacid and extracted with ether (3×25 ml). These extracts were washedsuccessively with water (3×20 ml) and saturated brine (20 ml), thendried (MgSO₄) and evaporated. The residue was purified by MPLC, elutingwith hexane/ethyl acetate/acetic acid (80:20:1 v/v), to give4(Z)-6-([2,4,5-cis]-2-cyclohexyloxymethyl-4-o-hydroxyphenyl-1,3-dioxan-5-yl)hexenoic acid as a clear oil which slowly crystallised to give solid(0.44 g) of m.p. 91°-93° C.; NMR: 1.28 (5H,m), 1.52 (1H,m), 1.73 (3H,m),1.92 (3H,m), 2.32 (4H,m), 2.66 (1H,m), 3.33 (1H,m), 3.65 (2H,d J=4 Hz),3.92 (1H,dm J=11 Hz), 4.14 (1H,dd J=11,1 Hz), 4.92 (1H,t J= 4 Hz), 5.26(1H,d J=2 Hz), 5.27 (1H,m), 5.44 (1H,m), 6.88 (3H,m), 7.16 (1H, tdJ=7,1.5 Hz), 8.50 (2H,br); m/e 422 (M⁺ +NH₄), 405 (M⁺ +H).

The necessary starting materials were prepared as follows:

(a) Cyclohexanol (11.00 g) was added slowly over 2 hours to a stirredsuspension of sodium hydride (4.80 g, 50% w/w dispersion in oil) in dryDMPU (100 ml) at 50° C. under argon. The mixture was stirred for anadditional 30 minutes, then cooled to 5° C. and treated with2-bromo-1,1-dimethoxyethane (16.9 g). Stirring was continued for 18hours at ambient temperature. The mixture was then poured into ice-water(250 ml). The aqueous mixture was extracted with ether (4×100 ml). Thecombined extracts were washed successively with water (3×100 ml) andsaturated brine (100 ml), then dried (MgSO₄) and evaporated. Flashchromatography of the residue, eluting successively with hexane, 5% v/vethyl acetate hexane and 10% v/v ethyl acetate/hexane, gave2-cyclohexyloxy-1,1-dimethoxyethane as an oil (A) (7.32 g). This wasused without further purification. [A sample was distilled under vacuum(bulb to bulb transfer); NMR: 1.29 (5H,m), 1.55 (1H,m), 1.76 (2H,m),1.92 (2H,m), 3.27 (1H,m), 3.40 (6H,s), 3.50 (2H,d J=5 Hz), 4.48 (1H,tJ=5 Hz).]

(ii) A stirred mixture of4(Z)-erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acid(1.40 g), p-toluenesulphonic acid (5 mg) and A (5.40 g) was heated at100° C. for 4 hours. The solution was cooled, methanol (10 ml) added andthe mixture stirred for 18 hours at ambient temperature. Triethylamine(1.40 g) was added and the solvent evaporated. The residue was purifiedby MPLC, eluting with 15% v/v ethyl acetate/hexane, to give methyl4(Z)-6-([2,4,5-cis]-2-cyclohexyloxymethyl-4-o-melthoxyphenyl-1,3-dioxan-5-yl)hexenoateas an oil (B) (0.97 g).

(iii) A solution of the ester B (0.97 g) in methanol (50 ml) washydrolysed using 2M potassium hydroxide (7 ml) for 18 hours inaccordance with the general procedure described in Example 2 (v). Therewas thus obtained, following MPLC of the crude product eluting withhexane/ethyl acetate/acetic acid (75:25:1 v/v),4(Z)-6-([2,4,5-cis]-2-cyclohexyloxymethyl-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid, as a clear oil (0.72 g); NMR: 1.26 (5H,m), 1.63 (4H,m), 1.94(3H,m), 2.27 (4H,m), 2.47 (1H,m), 3.34 (1H,m), 3.66 (2H,d J=4 Hz), 3.80(3H,s), 3.95 (1H,dm J=11 Hz), 4.08 (1H,br d J=12 Hz), 4.94 (1H,t J=4Hz), 5.21 (1H,d J=2 Hz), 5.27 (2H,m), 6.83 (1H,br d J=7), 6.96 (1H, br tJ=7 Hz), 7.23 (1H,td J=7,1.5 Hz), 7.40 (1H, dd J=7,1 Hz).

EXAMPLE 5

Using a similar procedure to that described in Example 4, but startingfrom4(Z)-6-([2,4,5-cis]-4-o-methoxyphenyl-2-phenoxymethyl-1,3-dioxan-5-yl)hexenoicacid, there was obtained4(Z)-6-([2,4,5-cis]-4-o-hydroxyphenyl-2-phenoxymethyl-1,3-dioxan-5-yl)hexenoicacid as a sticky solid in 75% yield; NMR: 1.77 (1H,m), 1.92 (1H,m), 2.31(4H,m), 2.68 (1H,m), 4.00 (1H,dm J=11 Hz), 4.16 (2H,d J=4 Hz), 4.19(1H,br d J=11 Hz), 5.16 (1H, t J=4 Hz), 5.31 (1H,d J=2 Hz), 5.36 (2H,m),6.50 (1H,6), 6.92 (6H,m), 7.16 (1H,td J=7,1.5 Hz), 7.29 (2H,m); m/e 398(M⁺).

The starting material was obtained as follows:

A mixture of4(Z)-erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acid(792 mg), p-toluene sulphonic acid (5 mg) and2-phenoxy-1,2-dimethoxyethane (2.72 g) was stirred at 80° C. for 3hours. The mixture was cooled and diluted with ether (25 ml) and thenextracted with 0.2M sodium hydroxide (3 ×15 ml). The aqueous extractswere acidified to pH5 with acetic acid and extracted with ether (3×20ml). These extracts were washed successively with water (2×15 ml) andsaturated brine (15 ml), then dried (MgSO₄) and evaporated. The residuewas purified by MPLC, eluting with hexane/ethyl acetate/acetic acid(75:25:1 v/v), to give4(Z)-6-([2,4,5,cis]-4-o-methoxyphenyl-2-phenoxymethyl-1,3-dioxan-5-yl)hexenoicacid, as a clear oil (229 mg); NMR: 1.63 (1H, m), 1.90 (1H,m), 2.29(4H,m), 2.50 (1H,m), 3.81 (3H,s), 4.00 (1H,dm J=11 Hz), 4.22 (1H,br dJ=11 Hz), 4.17 (2H,d J=4 Hz), 5.18 (1H,t J=4 Hz), 5.28 (1H,d J=2 Hz),5.31 (2H,m), 6.91 (5 H,m), 7.25 (3H,m), 7.41 (1H,dd J=7,1.5 Hz).

EXAMPLE 6

A stirred solution of4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid (584 mg) in dry (THF) (5 ml) was treated at 4° C. under argon witha solution of lithium diphenylphosphide [prepared fromchlorodiphenylphosphine (1.44 ml) and lithium metal (224 mg) in dry THF(8 ml)]. The mixture was stirred for 5 minutes at 4° C., then for 3.5hours at 55° C., cooled to 10° C. and added to ice-water (100 ml). Theaqueous solution was washed with ether (2 ×50 ml), acidified to pH5 withacetic acid and extracted with ether (3×50 ml). These extracts werewashed successively with water (2×50 ml) and saturated brine (50 ml),then dried (MgSO₄) and evaporated. The residue was purified by MPLC,eluting with hexane/ethyl acetate/acetic acid (85:15:1 v/v), to give4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-hydroxyphenyl-1,3-dioxan-5-yl)hexenoicacid as a clear oil (426 mg); NMR (90 MHz): 1.36 (6H,bs), 1.88 (2H,m),2.36 (4H,m), 2.68 (1H,m), 3.96 (1H,dm J=11 Hz), 4.23 (1H,bd J=11 Hz),4.80 (1H,s), 5.33 (1H,d J=2 Hz), 5.38 (2H,m), 7.06 (9H,m), 8.50 (2H,b);m/e 444 (M⁺ +NH₄), 427 (M⁺ +H).

The starting material was obtained as follows:

A suspension of4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoic acid(1.5 g) in 2-methyl-2-phenoxypropionaldehyde (3.0 g) containingp-toluenesulphonic acid (10 mg) was stirred for 18 hours at ambienttemperature and then heated at 60° C. for 6 hours. The cooled solutionwas diluted with ether (30 ml) and extracted with 0.5M sodium hydroxidesolution (3 ×10 ml). The aqueous extracts were washed with ether (20ml), then acidified to pH5 with acetic acid and extracted with ether(3×15 ml). These extracts were washed successively with water (2×10 ml)and saturated brine (10 ml), then dried (MgSO₄) and evaporated. Theresidue was purified by MPLC, eluting with hexane/ethyl acetate/aceticacid (85:15:1 v/v), to give4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid as a clear oil (655 mg); NMR: 1.34 (3H,s), 1.42 (3H,s), 1.57(1H,m), 1.89 (1H,m), 2.30 (4H,m), 2.49 (1H,m), 3.81 (3H,s), 3.98 (1H,dmJ=11 Hz), 4.15 (1H,dd J=11,1 Hz), 4.80 (1H,s), 5.24 (1H, d J=2 Hz), 5.32(2H,m), 6.85 (1H,ddJ=7,1 Hz), 7.03 (4H,m), 7.24 (3H,m), 7.43 (1H,ddJ=7,1.5 Hz); m/e 458 (M⁺ +NH₄), 441 (M⁺ +H).

The necessary 2-methyl-2-phenoxypropionaldehyde was itself obtained asfollows:

A stirred solution of methyl 2-methyl-2-phenoxypropionate (3.88 g) indichloromethane (100 ml) was treated dropwise at -70° C. under argon,with a 1M solution of diisobutylaluminium hydride (dibal) indichloromethane (21 ml). The solution was stirred for 1 hour at -70° C.,then allowed to warm to -30° C., after which it was poured into avigourously stirred aqueous solution of potassium sodium tartratetetrahydrate (50 g) dissolved in water (100 ml) cooled to 4° C. Afterstirring for 30 minutes, the mixture was separated by filtration throughdiatomaceous earth. The filtrate was extracted with ether (4×100 ml) andthe extracts were washed with saturated brine (2×100 ml), dried (MgSO₄)and evaporated. The residual oil (3.18 g) containing2-methyl-2-phenoxypropionaldehyde was used without further purification.

EXAMPLE 7

A stirred solution of4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-propoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid (803 mg) in dry THF (2 ml) was treated at 4° C. under argon with asolution of lithium diphenylphosphide [prepared fromchlorodiphenylphosphine (1.80 ml) and lithium metal (280 mg) in dry THF(10 ml)]. The mixture was stirred for 5 minutes at 4° C., then for 3hours at 50° C. cooled to 10° C. and added to ice-water (50 ml). Theaqueous solution was washed with ether/hexane (1:1 v/v) (3×25 ml),acidified to pH5 with acetic acid and extracted with ether (3×25 ml).These extracts were washed successively with water (2×25 ml) andsaturated brine (25 ml), dried (MgSO₄) and evaporated. The residue waspurified by MPLC, eluting with hexane/ethyl acetate/acetic acid (85:15:1v/v), to give4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-propoxyethyl]-4-o-hydroxyphenyl-1,3-dioxan-5-yl)hexenoicacid as a colourless oil *(650 mg); NMR: 0.90 (3H,t J=7 Hz), 1.25(3H,s), 1.26 (3H,s), 1.57 (2H,q J=7 Hz), 1.72 (1H,m), 1.92 (1H,m), 2.33(4H,m), 2.63 (1H,m), 3.41 (2H, td J=7,1 Hz), 3.88 (1H,dm J=11 Hz), 4.15(1H,dd J=11,1 Hz), 4.59 (1H,s), 5.25 (1H,d J=2 Hz), 5.38 (2H,m), 6.87(3H,m), 7.16 (1H,td J-7,1.5 Hz); m/e 392 (M⁺).

The necessary starting material was obtained as follows:

A suspension of4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoic acid(1.5 g) in 2-methyl-2-propoxypropionaldehyde (4 g) containingp-toluenesulphonic acid (10 mg) was stirred for 18 hours. The solutionobtained was diluted with ether (25 ml) and extracted with 0.2M sodiumhydroxide solution (3×25 ml). The aqueous extracts were acidified to pH5with acetic acid and extracted with ether (3×25 ml). These extracts werewashed successively with water (2×25 ml) and saturated brine (25 ml),then dried (MgSO₄) and evaporated. The residue was purified by MPLC,eluting with hexane/ethyl acetate/acetic acid (80:20:1 v/v) to give4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-propoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid as a clear oil (1.01 g); NMR: 0.88 (3H,t J-7 Hz), 1.27 (3H,s), 1.30(3H,s), 1.54 (2H,q J=7 Hz), 1.55 (1H,m), 1.84 (1H,m), 2.28 (4H,m), 2.43(1H,m), 3.46 (2H, t J=7 Hz), 3.80 3H,s) 3.90 (1H,dm J=11 Hz), 4.09 (1H,dd J=11 Hz), 4.64 1H,s), 5.19 (1H,d J=2 Hz), 5.28 (2H,m), 6.84 (1H,ddJ=7,1 Hz), 6.97 (1H,td J=7,1 Hz), 7.24 (1H,td J=7,1.5 Hz), 7.42 (1H,ddJ=7,1.5 Hz); m/e (-VE FAB) 405 (M-H)⁻.

The 2-methyl-2-propoxypropionaldehyde required as starting material wasobtained as a clear oil (4.0 g) in an analogous manner to that describedin Example 1 (a) for 2-methyl-2-phenoxypropionaldehyde but starting fromthe known compound methyl 2-methyl-2-propoxypropionate (3.8 g).

EXAMPLE 8

Using a similar procedure to that described in Example 4, but startingfrom4(Z)-6-([2,4,5-cis]-4-o-methoxyphenyl-2-[1-butoxyethyl]-1,3-dioxan-5-yl)hexenoicacid, there was obtained4(Z)-6([2,4,5-cis]-4-o-hydroxyphenyl-2-[1-butoxyethyl]-1,3-dioxan-5-yl)hexenoicacid as a clear oil in 92% yield; NMR: 0.91 (3H, t J=7 Hz), 1.24 (4H,m), 1.38 (1H, m), 1.56 (2H, m), 1.69 (1H, m), 1.90 (1H, m), 2.33 (4H,m), 2.66 (1H, m), 3.55 (3H, m), 3.90 (1H dm J=12 Hz), 4.15 (1H, d) J=11Hz), 4.73 (1H, 2d J=3 Hz), 5.24 (1H, d J=2 Hz), 5.35 (2H, m), 6.88 (3H,m), 7.17 (1H, m), 8.10 (1H, bs); m/e 393 (M⁺ +H).

The necessary starting material was obtained as follows:

(i) Sodium borohydride (2.84 g) was added portionwise over 30 minutes toa stirred solution of 3-ketobutyaldehyde dimethyl acetal (18.0 ml) inabsolute ethanol (75 ml), the temperature being maintained at 20°-25° C.with water cooling. The mixture was stirred for a further 2 hours atambient temperature was then poured into saturated ammonium chloride.The subsequent mixture was extracted with ether (3×100 ml). The extractswere washed with saturated brine (50 ml), dried (MgSO₄) and the solventevaporated to give 1,1-dimethoxy-2-propanol (A) as a yellow oil; NMR (90MHz): 1.20 (3H, d J=6 Hz), 2.30 (1H, bs), 3.42 (3H, s), 3.47 (3H, s),3.75 (1H, m), 4.08 (1H, d J=6 Hz).

(ii) A solution of A (3.75 g) in DMPU (2 ml) was added dropwise underargon to a stirred suspension of sodium hydride (0.75 g) in DMPU (25ml). The mixture was heated to 50° C. for 30 minutes, then cooled to 10°C. and butyl bromide (3.7 ml) added. Stirring was continued overnightand then water (100 ml) was added. The mixture was extracted with ether(3×50 ml). The extracts were washed with water (50 ml), brine (50 ml),dried (Mg SO₄) and the solvent evaporated. The residue was purified byflash chromatography, eluting with 10% v/v ethyl acetate/hexane to give1,1-dimethoxy-2-butoxypropane (B) as a clear oil (1.8 g); NMR (90 MHz):0.8-1.8 (10H, m), 3.50 (9H, m), 4.15 (1H, d J=5 Hz).

(iii) Using a similar procedure to that described in Example 4(ii) and(iii), but starting from 1,1-dimethoxy-2-butoxypropane (B), there wasobtained4(Z)-6-([2,4,5-cis]-4-o-methoxyphenyl-2-[1-butoxyethyl]-1,3-dioxan-5-yl)hexenoicacid, as a clear oil in 49% yield; NMR: 0.91 (3H, m), 1.28 (3H, t J=6Hz), 1.35 (2H, m), 1.57 (3H, m), 1.85 (1H, m), 2.36 (5H, m), 3.58 (3H,m), 3.80 (3H, s), 3.93 (1H, dm J=11 Hz), 4.09 (1H, bd J=11 Hz), 4.73(0.5H, d J=3 Hz), 4.83 (0.5H, d J=3 Hz), 5.29 (3H, m), 6.84 (1H, d J=7Hz), 6.97 (1H, t J=7 Hz), 7.24 (1H, bt J=7 Hz), 7.42 (1H, m); m/e 406(M⁺).

EXAMPLE 9

Using a similar procedure to that described in Example 6, but startingfrom(-)-4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid (A), there was obtained(-)-4(Z)-6-([2,4,5-cis]-4-o-hydroxyphenyl-2-[1-methyl-1-phenoxyethyl]-1,3-dioxan-5-yl)hexenoicacid in 64% yield as a colourless oil; NMR essentially the same as forthe racemate (Example 6); m/e 427(M⁺ +H); ²⁰ [α]_(D) -129.9° (c, 0.85;methanol).

The starting material A was obtained as follows:

(i) Solid potassium t-butoxide (4.48 g) was added under argon to astirred, ice-cooled mixture of (3-carboxypropyl)triphenylphosphoniumbromide (6.44 g) and(-)-[2,3-trans]-tetrahydro-5-hydroxy-3-hydroxymethyl-2-o-methoxyphenylfuran(B) (2.24 g) in dry THF (75 ml). The mixture was stirred for 15 minutesat 4° C., then for 1 hour at ambient temperature and was then pouredinto ice-water (150 ml). The mixture obtained was washed with ether(2×50 ml) to remove the bulk of the neutral material. The aqueous phasewas acidified to pH4 with 1M hydrochloric acid and extracted with ether(1×100 ml, 2×50 ml). These combined extracts were washed successivelywith water (2×50 ml) and saturated brine (2×50 ml), then dried (MgSO₄)and evaporated. The residue was purified by flash chromatography,eluting with ether/hexane/acetic acid (80:20:1 v/v) to give(-)-erythro-4(Z)-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoicacid (C) as a colourless oil (2.76 g); ²² [α]_(D) -68.3° (c 1.1,methanol); NMR: 1.92 (1H,m), 2.0-2.6 (6H,m), 3.67 (2H,m), 3.82 (3H,s),5.21 (1H,d J=5 Hz), 5.37 (2H,m), 6.87 (1H,dd J=8,1 Hz), 6.98 (1H,tdJ=7,1 Hz), 7.25 (1H,m), 7.42 (1H,dd J=7,1 Hz); m/e 294 (M⁺).

(ii) A solution of C (2.57 g) in 2,2-dimethoxypropane (8.5 ml) wastreated with `Amberlyst`-15 (Trademark of Rohm and Haas Company)strongly acid, macroreticular ion-exchange resin (0.5 g) and the mixturestirred for 21/2 hours at ambient temperature. The solid was removed byfiltration and washed with ether (10 ml). The filtrate and washings wereconcentrated in vacuo and the residue was purified by MPLC, eluting withhexane/ethyl acetate/acetic acid (80:20:1 v/v). A clear oil was obtainedwhich slowly crystallised to give(-)-4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoicacid (D) (2.48 g). Recrystallisation from hexane gave solid of m.p.71°-73° C., ²³ [α]_(D) -145.5° (c 1.1, methanol) with an NMR spectrumessentially the same as that of the corresponding racemate (Compound Ain Ex. 2).

(iii) The hexenoic acid D was reacted with2-methyl-2-phenoxypropionaldehyde using the same procedure as describedfor the corresponding racemate in Example 6. There was thus obtained(-)-4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid as a colourless oil in 21% yield, having an NMR spectrumessentially the same as that of the racemic starting material describedin Example 6.

The furan derivative B was itself obtained as follows:

(iv) Succinic anhydride (22 g), o-methoxybenzaldehyde (20 g) andanhydrous zinc chloride (44 g) were added to dichloromethane (dried overalumina, 200 ml) and the mixture stirred under argon. Triethylamine (41ml) was added to the ice-cooled mixture over a period of 20 minutes. Thereaction mixture was then stirred at 20°-25° C. for 18 hours, afterwhich time hydrochloric acid (2M, 130 ml) and ethyl acetate (200 ml)were added. The subsequent mixture was stirred for 5 minutes. Theaqueous phase was separated and extracted with ethyl acetate (150 ml).The combined extracts were washed with saturated brine (50 ml) and thenextracted with saturated sodium bicarbonate solution (3×200 ml). Thecombined aqueous extracts were washed with ethyl acetate, and thenacidified to pH2 with concentrated hydrochloric acid. The oil whichseparated was extracted into ethyl acetate (2×150 ml). The combinedextracts were washed with saturated brine (4×50 ml) until acid free,then dried (MgSO₄) and evaporated. Toluene (300 ml) was added to theresidue and the mixture was distilled atmospheric pressure until theresidual material attained 110° C. On cooling to 20° C.,tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarboxylic acid separated as acrystalline white solid (27.2 g, 78%) (m.p. 106° C.) which was shown byNMR to be a mixture of [2,3-cis-]-and [2,3-trans]-isomer: 2.8-3.0(2H,m), 3.1-3.6 (1H,m), 3.8 (3H,s), 5.82 (3/4H,d) [trans], 5.95 (1/4H,d) [cis], 6.8-7.5 (4H,m).

(v) A mixture of [2,3-cis]- and[2,3-trans]-tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarboxylic acid(188.6 g) was added to an ice cooled solution of concentrated sulphuricacid (320 ml) in water (480 ml) and stirred at 20°-25° C. for 18 hours.Water (800 ml) was then added and the mixture extracted with ethylacetate (2×750 ml). The combined extracts were washed with brine (4×500ml) until acid free, dried (MgSO₄) and evaporated to low volume. Toluene(1 liter) was added and the distillation continued at atmosphericpressure until the residual material attained a temperature of 110° C.On cooling pure[2,3-trans]-tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarboxylic acidseparated as a white crystalline solid (169.5 g, 90%), m.p. 133°-134°C.; NMR: 2.8-3.0 (2H,d), 3.3-3.6 (1H,m), 3.8 (3H,s), 5.82 (1H,d),6.8-7.4 (4H,m).

(vi) A solution of d-ephedrine (61.2 g) in hot ethyl acetate (150 ml)was added to a solution of[2,3-trans]-tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarboxylic acid(87.6 g) in hot ethyl acetate (350 ml). The mixture was allowed to coolto room temperature during 2 hours and the crystalline salt which hadformed was separated by filtration to give 62 g of solid material having²⁵ [α]_(D) +40.2° (methanol). This material was recrystallised twicefrom ethyl acetate to give 48 g of optically pure solid ²⁵ [ ]_(D)+50.3° (methanol). This solid was added to ethyl acetate (1 liter) and2M hydrochloric acid (150 ml). The ethyl acetate layer was washed withbrine (2×100 ml) until the pH of the washings was pH2-3, and then dried(MgSO₄) and evaporated. The residue was dissolved in boiling toluene(200 ml). Insoluble material was removed by hot filtration. The filtratewas allowed to cool to give(+)-[2,3-trans]-tetrahydro-2-o-methoxyphenyl-5-oxo-3-furancarboxylicacid (E) (27.4 g) ²⁵ [α]_(D) +33.0° (methanol). Recrystallisation fromtoluene gave material of ²⁵ [α]_(D) +33.8° (methanol), m.p. 125°-127° C.(decomposition), shown to be <98% optically pure by conversion of asmall sample to its (-)-amyl ester and examination of the ¹³ C NMRspectrum.

(vii) A solution of E (97.5 g) in dry tetrahydrofuran (150 ml) wascooled to 15° C. and treated with a solution of borane intetrahydrofuran (500 ml) of a 1M solution) with the temperaturemaintained at 20°-25° C. After 30 minutes the reaction was complete (asjudged by TLC analysis) and water (200 ml) was added slowly to decomposethe excess borane. The mixture was concentrated in vacuo and the residuewas mixed with ethyl acetate (500 ml). The organic layer was washedsuccessively with saturated potassium carbonate solution (2×100 ml) andsaturated brine, dried (MgSO₄), and evaporated to give[4,5-trans]-tetrahydro-4-hydroxymethyl-5-o-methoxyphenylfuran-2-one (F)as a viscous oil (81.8 g), having ²⁵ [α]_(D) -14.2° (methanol) and asatisfactory NMR spectrum (d₆ -acetone): 2.6 (3H,m), 3.7 (2H,m), 3.8(3H,s), 4.1 (1H,br), 5.55 (1H,m), 6.8-7.5 (4H,m).

(viii) A solution of F (obtained above) in 1,2-dimethoxyethane (150 ml)and dry toluene (500 ml) was cooled under a nitrogen atmosphere to -60°C. A toluene solution of diisobutylaluminium hydride (672 ml of 1.23Msolution) was then added slowly. After 30 minutes the reaction wasquenched by addition of methanol (50 ml) and the mixture allowed to warmup to room temperature. 2M Hydrochloric acid (1liter) and ethyl acetate(500 ml) were then added and the mixture stirred. The aqueous phase wasseparated and extracted with ethyl acetate (2×500 ml). The ethyl acetatephase and extracts were combined, dried (MgSO₄) and evaporated. Theresidual oil was dissolved in hot toluene (500 ml). The solutionobtained gave on cooling(-)-[2,3-trans]-tetrahydro-5-hydroxy-3-hydroxymethyl-2-o-methoxyphenylfuran(B) as a white solid (63.3 g), ²⁵ [α]_(D) -24.2° (methanol), m.p.110°-111° C.; NMR: 1.5-2.4 (3H,m), 3.4-4.0 (2H,m), 3.8 (3H,s), 4.2-4.8(2H,br), 5.25 (1H, m), 5.6 (1H, m), 6.9-7.9 (4H, m).

EXAMPLE 10

Illustrative pharmaceutical dosage forms include the following table,capsule, injection and aerosol formulations, which may be obtained byconventional procedures well known in the art of pharmacy and aresuitable for therapeutic or prophylactic use in humans:

    ______________________________________                                        (a) Tablet I             mg/tablet                                            ______________________________________                                        Compound X*              1.0                                                  Lactose Ph. Eur.         93.25                                                Croscarmellose sodium    4.0                                                  Maize starch paste (5% w/v aqueous paste)                                                              0.75                                                 Magnesium stearate       1.0                                                  ______________________________________                                    

    ______________________________________                                        (b) TABLE II             mg/tablet                                            ______________________________________                                        Compound X*              50                                                   Lactose Ph. Eur          223.75                                               Croscarmellose sodium    6.0                                                  Maize starch             15.0                                                 Polyvinylpyrrolidone (5% w/v aqueous paste)                                                            2.25                                                 Magnesium stearate       3.0                                                  ______________________________________                                    

    ______________________________________                                        (c) TABLE III            mg/tablet                                            ______________________________________                                        Compound X*              100                                                  Lactose Ph. Eur.         182.75                                               Croscarmellose sodium    12.0                                                 Maize starch paste (5% w/v aqueous paste)                                                              2.25                                                 Magnesium stearate       3.0                                                  ______________________________________                                    

    ______________________________________                                        (d) Capsule      mg/capsule                                                   ______________________________________                                        Compound X*      10 mg                                                        Lactose Ph.Eur.  488.5                                                        Magnesium stearate                                                                              1.5                                                         ______________________________________                                    

    ______________________________________                                        (e) Injection I      (50 mg/ml)                                               ______________________________________                                        Compound X* (free acid form)                                                                        5.0% w/v                                                1 M Sodium hydroxide solution                                                                      15.0% v/v                                                0.1 M Hydrochloric acid                                                       (to adjust pH to 7.6)                                                         Polyethylene glycol 400                                                                             4.5% w/v                                                Water for injection to 100%                                                   ______________________________________                                    

    ______________________________________                                        (f) Injection II     (10 mg/ml)                                               ______________________________________                                        Compound X* (free acid form)                                                                        1.0% w/v                                                Sodium phosphate EP   3.6% w/v                                                0.1 M Sodium hydroxide                                                                             15.0% v/v                                                solution                                                                      Water for injection to 100%                                                   ______________________________________                                    

    ______________________________________                                                            (1 mg/ml, buffered                                        (g) Injection III   to pH 6)                                                  ______________________________________                                        Compound X* (free acid form)                                                                      0.1% w/v                                                  Sodium phosphate BP 2.26% w/v                                                 Citric acid         0.38% w/v                                                 Polyethylene glycol 400                                                                           3.5% w/v                                                  Water for injection to 100%                                                   ______________________________________                                    

    ______________________________________                                        (h) Aerosol I      mg/ml                                                      ______________________________________                                        Compound X         10.0                                                       Sorbitan trioleate 13.5                                                       Trichlorofluoromethane                                                                           910.0                                                      Dichlorodifluoromethane                                                                          490.0                                                      ______________________________________                                    

    ______________________________________                                        (i) Aerosol II      mg/ml                                                     ______________________________________                                        Compound X*         0.2                                                       Sorbitan trioleate  0.27                                                      Trichlorofluoromethane                                                                            70.0                                                      Dichlorodifluoromethane                                                                           280.0                                                     Dichlorotetrafluoroethane                                                                         1094.0                                                    ______________________________________                                    

    ______________________________________                                        (j) Aerosol III     mg/ml                                                     ______________________________________                                        Compound X*         2.5                                                       Sorbitan trioleate  3.38                                                      Trichlorofluoromethane                                                                            67.5                                                      Dichlorodifluoromethane                                                                           1086.0                                                    Dichlorotetrafluoroethane                                                                         191.6                                                     ______________________________________                                    

    ______________________________________                                        (k) Aerosol IV      mg/ml                                                     ______________________________________                                        Compound X*         2.5                                                       Soya lecithin       2.7                                                       Trichlorofluoromethane                                                                            67.5                                                      Dichlorodifluoromethane                                                                           1086.0                                                    Dichlorotetrafluoroethane                                                                         191.6                                                     ______________________________________                                    

Note

The tablet compositions (a)-(c) may be enteric coated by conventionalmeans, for example to provide a coating of cellulose acetate phthalate.The aerosol compositions (h)-(k) may be used in conjunction withstandard, metered dose aerosol dispensers, and the suspending agentssorbitan trioleate and soya lecithin may be replaced by an alternativesuspending agent such as sorbitan monooleate, sorbitan sesquioleate,polysorbate 80, polyglycerol oleate or oleic acid. ##STR1##

What is claimed is:
 1. A compound of the formula VIwherein R¹ is(1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, phenyl orphenyl-(1-4C)alkyl, the latter two of which may optionally bear one ortwo substituents selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy,hydroxy, trifluoromethyl, nitro and cyano; R² and R³ are independentlyhydrogen or (1-4C)alkyl, or together form (3-6C)polymethylene optionallybearing one or two (1-4C)alkyl substituents; R" is (1-6C)alkyl, p is 0,1 or 2, n is 1, m is 2 or 3 and Z is carboxy, and the groups atpositions 2, 4 and 5 of the dioxane ring have cis-relativestereochemistry or a salt thereof.